Most vasoactive hormones (excluding beta adrenergic) appear to act on vessels and their derivatives (JG cells) after receptor activation by phosphatidylinositol breakdown (Pl) followed by activation of Ca-calmodulin-protein kinase C (PK-C) systems. In addition, Ca activation of membrane phospholipases also leads to the release of free arachidonic acid (AA) and potential formation of both cyclooxygenase (CO) and lipoxygenase (LO) products. The products of CO (PGl2) and recently LO (12 and 15-HETES) pathways have been shown to be made by both glomerulus and vascular tissue. We have new evidence that 12 and 15-HETES are potent inhibitors (10-10 M-10-8M) of renin release. We wish to, 1) complete and fully characterize the role of LO pathway in renin release. Our work to date (unpublished), suggests the presence of a dual system for renin release; whereby, AA may be metabolized to either secretagogue (prostaglandins) or an inhibitor (HETES, via LO path) and this balance may be a key regulator in normal and abnormal (i.e. diabetic) renin states. 2) Since following angiotensin II action, via Ca++, rapid turnover of Pl may also serve as the initial source of free AA. Metabolites of AA (PGs or LO products) may play an important role in the functioning of the calcium messenger system. We will study whether LO products (HETES) of prostaglandins are involved in All inhibition of renin. Exciting preliminary date suggest that the LO inhibitor, BW755c, blocks All action on renin with or without indomethacin (CO blocker). Using specific HPLC and RIA methods for measuring picogram amounts of PGl2 and HETE (12 and 15), we can study the effect of All on renal cortical slices and enriched JG cell preparations in our perifusion set up. 3) Our group has published reports that vasoactive prostaglandins enhance and cyclooxygenase blockers prevent the reciprocal drop in inactive to active renin in plasma in patients. We plan on studying whether prostaglandins activate and LO products inhibit the mechanisms (? protease) for the conversion of the pro or inactive to active renin using rabbit JB cells. 4) Finally, using agonists and antagonists of the calcium-calmodulin-PK-C, we will determine whether prostaglandins and HETES act via this messenger system. Our studies should clarify a major confusion in the field: How calcium can enhance AA formation in vascular tissue, yet lead to renin suppression. Our explanation is that the LO pathway is activated and our work may extend our current knowledge of angiotensin biochemistry and the synthesis of renin from its precursors.